Proton pump inhibitors (PPIs) are agents having powerful inhibitory action against H+/K+-adenosine triphosphate (ATP) and prevent secretion of gastric acid. For example, Pantoprazole sodium is a proton pump inhibitor and is pharmaceutically used in short-term treatment (7 to 10 days) of Gastroesophageal Reflux Disease (GERD) associated with a history of erosive esophagitis as well as for the treatment of pathological hypersecretory conditions including Zollinger-Ellison Syndrome in adults. These Proton pump inhibitors are generally reported to be acid labile compounds/derivatives.
Pantoprazole sodium, is a substituted benzimidazole derivative and is chemically known as sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole. In various marketed formulations crystalline sesquihydrate polymorphic form is used. Sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H benzimidazole sesquihydrate is represented by the following formula:
Following formulations of Pantoprazole sodium are approved in the USA:(I) 20 & 40 mg delayed release tablets(II) i.v. infusion formulation (Eq 40 mg base/vial)(III) Delayed release granules for oral suspension (Eq 40 mg base)
Patent publication U.S. Pat. No. 4,758,579 is assigned to Nycomed which covers Pantoprazole as a product.
Pantoprazole sodium sesquihydrate delayed release granules for oral suspension are marketed in the USA under the brand name PROTONIX® and contain crospovidone, hypromellose, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, povidone, sodium carbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow ferric oxide as the inactive ingredients. For patients having difficulty in swallowing, such as pediatric and geriatric patients, oral liquid formulations such as suspension is the preferred dosage form. Pantoprazole sodium sesquihydrate delayed release granules for oral suspension can be administered by sprinkling the granules on one teaspoonful of applesauce or empty granules into a small cup or teaspoon containing one teaspoon of apple juice and consume this within 10 minutes of preparation.
Patent publication U.S. Pat. No. 5,997,903 is assigned to Byk Gulden discloses oral delayed release tablet dosage forms of Pantoprazole.
Patent publication U.S. Pat. No. 8,865,212 is assigned to Jubilant Generics Ltd. discloses non-multiple unit pellet system (MUPS) of an acid labile benzimidazole derivative in tablet dosage forms devoid of disintegrant.
Patent publications U.S. Pat. Nos. 7,544,370, 7,550,153, 7,553,498 and 7,838,027 are assigned to Wyeth and listed in Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) disclose multiparticulate formulation of Pantoprazole. As per the disclosure of these patent publications, the benzimidazole derivatives employed as proton pump inhibitors are easily destroyed in the acid milieu and thus are difficult to formulate for oral administration. These patent publications highlight various formulation challenges associated with multiparticulate formulation of Pantoprazole such as, stability issues at room temperature, inappropriate release under acid conditions and adherence to the intestinal walls, nasogastric and gastronomy tubes. As per these patent publications, the desired formulation was achieved by essentially using the following proportion of pharmaceutical excipients:
IngredientsRange% w/w of the corePantoprazole sodiumabout 45%45.24Microcrystalline celluloseabout 25 to 30%27.25Polysorbate 80about 4 to 6%5Crospovidoneabout 14 to 16%15Hypromelloseabout 0.5 to 2%1Sodium carbonateabout 5 to 8%6.5
Multiparticulate formulations of proton pump inhibitor are prepared by mixing disintegrant(s) and surfactant for consistent and satisfactory dissolution of drug from the dosage form. Disintegrants are often considered as most important, as they ensure the break-up of the dosage form into smaller fragments upon ingestion, to allow the onset of drug dissolution and eventual absorption. Disintegrants are often associated with promoting moisture penetration into the matrix of core of the dosage form to initiate the disintegration process. The disintegration process can mechanistically be subdivided into stages, breakdown into coarse aggregates and subsequent deaggregation into fine primary particles which subsequently increases the surface area.
Surfactants used in enteric coated dosage forms, provide better wettability and enhance the solubility of the drug, which improves the dissolution property. On the other hand, higher amount of surfactant can also cause gastric irritation. As per patent publication listed in Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) by the innovator for the desired technical attributes, disintegrant is used in the range of 14-16% w/w and surfactant is used in the range of 4-6% w/w, which is very high.
Surprisingly, it is found by the inventors of the present invention that multiparticulate compositions of benzimidazole compounds, particularly Pantoprazole compositions, can be prepared by varying the amount of essential excipients like disintegrant and surfactant. Further, by avoiding the higher amount of disintegrant and/or using lesser amount of surfactant desired pharmaceutical technical attributes were achieved like drug release, assay, stability, no polymorphic change, reduced or no sticking to nasogastric and gastronomy tubes, and packaging material.